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It seems like with HIV they can simply sequence the prevalent evolutionary outcome in your body within a month and give your body the blueprint to destroy that version

What typically happens with HIV is that the body kills most of it initially, but the remaining ones keep rapidly evolving until an iteration evades your immune response, this takes about 12 years. Seems like an mRNA vaccine could be done every 3 years for individuals and either completely eradicate the HIV presence in the body or do it once every 12 years for a reset

Let me know if I fundamentally misunderstand something

That's not quite true - HIV of course mutates but in-patient mutations are generally considered to have a negligible effect on outcomes/have a negligible effect as a driver of morbidity .

What is the big driver of HIV is in the name, it's a Immunodeficiency virus - it kills CD4+ T cells and other cells of the immune system. At a certain point you don't have enough CD4+ T cells left and you lose your adaptive/cell-mediated immune system and then you're in big trouble. Essentially it's a war of attrition and unless you're part of some tiny proportion of people who have either a form of immunity against it or an immune system that for whatever reason is able to continue waging war on it then you will succumb

> by the time the vaccines are ready for distribution, a different strain may have emerged as the better target

I have never understood this. How many strains are there? I thought there were only like 4 or so. Why don't they just do them all every year?

There are subtypes of each. Influenza A and B cause the seasonal flu. The subtypes are named by their hemagglutinin (H) and neuraminidase (N). E.g. H1N1, H5N9, etc.

OK, but that doesn't really answer my question.

Turns out the answer can be found here:

https://www.cdc.gov/flu/about/viruses/types.htm

"There are four types of influenza viruses: A, B, C and D. Human influenza A and B viruses cause seasonal epidemics of disease (known as the flu season) almost every winter in the United States. Influenza A viruses are the only influenza viruses known to cause flu pandemics, i.e., global epidemics of flu disease. A pandemic can occur when a new and very different influenza A virus emerges that both infects people and has the ability to spread efficiently between people. Influenza type C infections generally cause mild illness and are not thought to cause human flu epidemics. Influenza D viruses primarily affect cattle and are not known to infect or cause illness in people."

"Influenza A viruses are divided into subtypes based on two proteins on the surface of the virus: hemagglutinin (H) and neuraminidase (N). There are 18 different hemagglutinin subtypes and 11 different neuraminidase subtypes (H1 through H18 and N1 through N11, respectively). While there are potentially 198 different influenza A subtype combinations, only 131 subtypes have been detected in nature. Current subtypes of influenza A viruses that routinely circulate in people include: A(H1N1) and A(H3N2). Influenza A subtypes can be further broken down into different genetic “clades” and “sub-clades.” See the “Influenza Viruses” graphic below for a visual depiction of these classifications."

So the answer is: 198 possible strains, 131 that actually occur. That explains why they have to pick and choose.

I don't think that's quite right. Even if you have a flu strain with a particular name (H1N1) there are a number of variants within the H1 and/or N1 proteins that the vaccine will be targeted to as well, so the number is quite a bit larger than 198/131.

It's not that hard to make a new vaccine, the process for flu is very accelerated because they're just a variation on the original theme which has been proven to be safe (though unclear on effective until AFTER the flu season hits). If you think about it, we make a new flu vaccine every year, and develop it in 6 months. Each one contains a few guesses as to which of the flus are going to be an issue, it's not just one antigen in the vaccine. Those guesses are just that, an informed prediction, which is why the vaccines tend to be fairly ineffective (40-60%) at preventing disease altogether, though perhaps better at preventing serious disease.

Moderna is claiming to be quicker, so they'd have a more accurate read on what the REAL flu strain this year is going to be, and so it should be more efficacious. The key variable will be dosing. mRNA vaccines can only deliver a certain amount of mRNA so it might be impractical to deliver very many antigens at once. Also delivery issues, the current flu vaccine is super easy to make and deliver to patients, mRNA vaccines with their complicated cold chains aren't. Obviously it's not an impossible problem, but it's less convenient.

Time will tell, it's certainly very promising!

Helpful: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3619640/

It would be especially worth it to have approved mRNA flu vaccine in hand for the next pandemic flu. You'd might be able to actually vaccinate your way out of it.

It seems they could pre-make vaccines for all 131 extant types and then mix the flu shots based on the current season. Though, likely that wouldn’t be economical.

It does raise the question of why they couldn’t just put a bit of all 131 subtypes in the vaccine. Or if that’d overload the immune system, say, the X subtypes most likely to makeup say 99% of probable flu season strains.

They could - but up until recently no one cared enough, both for R&D spend and to get or mandate enough shots for it to work at it’s stated goals.

We’ve had people even recently refusing to give their kids polio, tetanus, or measles vaccines - and even 5 minutes of honest research or questions to a doctor will make quite clear how bad an idea THAT is. Getting 100+ flu vaccines, all which would have to go through a pipeline taking nearly a decade, when ‘nothing bad has happened’ on that topic for a hundred years?

Ain’t nobody going to pay for that.

We’ll see how the calculus is different soon. I for one would rather my tax dollars go towards figuring something like never having the flu again than blowing up some random middle eastern country a couple more times.

There’s got to be a large market for that given the entire elderly population is offered a flu shot every year. Doing that as a one off would be a huge cost saving.

Not sure it would pay for itself even in 100 years if you use that metric.

$20 (likely current retail cost of a flu shot) x the 46 million older adults in the US is a hair less than a billion a year. Making 131 or so effective flu vaccines and getting them through the process with the prior known and effective process? (including all the failed attempts)

Hopefully we’d get some economies of scale, estimates [https://www.passporthealthusa.com/2018/02/how-much-does-it-c...] I found had it between 500m to 2.5billion and a decade each. So 65billion to 327billion.

So between 65 to 327 years for positive ROI if that was your metric.

If you’re talking public good, it would be immeasurable for us and the world though, no question, and on the high end that’s less than a third [https://www.google.com/amp/s/www.bbc.co.uk/news/world-473918...] of what we’ve spent in Afghanistan alone.

I believe they’d make one shot that would handle 131 flus.

That would be ideal - we also have no evidence that is possible at all, or desirable with immune system behavior/interactions.

We'd need try to find out, which I personally think would be way better for everyone involved than many other things we spend money on. So take that as my vote for trying?

One more piece of this is they endlessly mutate, I don't think in reality there is a limit. Most mutations probably don't help the virus proliferate, might cause it to not be effective. Eventually the shape of a new one, what your body is looking for in it's remembered virus history will change enough that it can't be detected. We see this in real time with the cv19 variants. My mental model of this (I am in software so I welcome corrections to the applicability) is it's like antivirus in software - the bad guys making viruses keep trying new variations on old ones, switching what the protection software is looking for so they can get around detection methods, as well as trying to find new holes.

The lead time for pushing new "virus definitions" is a lot shorter once the vaccine is adopted and manufacturing chain is established. A central lab can download the new variants genome from labs all over the world, select some markers and push changes to manufacturing facilities through e-mail or even Git.

And those subtypes themselves are constantly mutating. Look at actual WHO vaccine recommendations:

https://www.who.int/influenza/vaccines/virus/recommendations...

They constantly mutate.

VaC (Vaccine as Code)